A substantial proportion of individuals with a clinical diagnosis of
Familial Hypercholesterolaemia (FH) inherit a combination of small-effect
changes in several genes (polygenic) rather than a large-effect mutation in a
single gene (monogenic), according to a new paper in The Lancet.

The findings have implications for the majority of national
guidelines on family screening for FH, that advocate testing relatives of all
individuals with a clinical diagnosis of FH, including those of the UK National
Institute for Health and Clinical Excellence (NICE).

We propose that the clinical diagnosis of FH should be restricted to those in
whom a mutation can be identified, whereas those with no detected mutation
should be given the clinical diagnosis of polygenic hypercholesterolaemia.

Professor Steve Humphries, UCL Centre for Cardiovascular
Genetics

FH is one of the most common inherited disorders affecting over 12
million people worldwide (1 in 500 of the general population). It causes very
high levels of low-density lipoprotein cholesterol (LDL-C) or “bad cholesterol”
in the blood, and if untreated, results in a five to eight times greater risk of
early coronary heart disease (CHD). Identification of patients with FH needs to
be improved because at least 75 per cent of cases remain undetected, untreated,
or improperly treated, despite good evidence that early detection and treatment
with statins can significantly improve life expectancy.

DNA-based cascade screening to identify other family members with FH,
who would benefit from treatment, has been recommended by NICE on the
presumption of a monogenic inheritance of the disorder, where first-degree
relatives would have a 50:50 chance of having the condition. However, 60 per
cent of people with clinically suspected FH have no identifiable mutation in any
of the three genes (LDLR, APOB, or PCSK9) known to cause FH.

“The current study was designed to investigate whether individuals
who inherit many small-effect, LDL-cholesterol raising sequence differences in a
wide range of genes might have received a clinical diagnosis of FH, which would
influence the efficacy of any cascade screening programme since the odds of
finding relatives with grossly elevated LDL-C in such cases would be less than
the expected 50 per cent," explains Professor Humphries.

Recent genetic studies have identified many common genetic variants
associated with a small increment in LDL-C levels. Genotyping for 12 of these
single nucleotide polymorphisms (SNPs) was done on blood samples from 321
mutation-negative UK patients with FH, as well as 319 UK patients with FH with a
known mutation, and 3,020 healthy individuals (controls) from the UK Whitehall
II study.

Each participant was assigned a weighted LDL-C-raising gene score
based on the number of risk-associated gene copies inherited. The results were
validated by repeating the analysis in a sample of over 700 patients with FH
from Belgium.

The findings showed that clinically suspected, but mutation negative
FH, was associated with inheritance of a greater than average number of
small-effect LDL-C-raising sequence differences.

Professor Humphries says: “We propose that the clinical diagnosis of
FH should be restricted to those in whom a mutation can be identified, whereas
those with no detected mutation should be given the clinical diagnosis of
polygenic hypercholesterolaemia. Both groups of patients will need statin
therapy, but the cost effectiveness of FH cascade testing will differ depending
on whether or not there is a polygenic or a single mutation cause.”